Mental programming of spatial sequences in working memory in the macaque frontal cortex.

How the brain mentally sorts a series of items in a specific order within working memory (WM) remains largely unknown. We investigated mental sorting using high-throughput electrophysiological recordings in the frontal cortex of macaque monkeys, who memorized and sorted spatial sequences in forward or backward orders according to visual cues. We discovered that items at each ordinal rank in WM were encoded in separate rank-WM subspaces and then, depending on cues, were maintained or reordered between the subspaces, accompanied by two extra temporary subspaces in two operation steps. Furthermore, the cue activity served as an indexical signal to trigger sorting processes. Thus, we propose a complete conceptual framework, where the neural landscape transitions in frontal neural states underlie the symbolic system for mental programming of sequence WM.

Spatial cognitive ability is associated with longevity in food-caching chickadees.

Cognitive abilities are hypothesized to affect survival and life span in nonhuman animals. However, most tests of this hypothesis have relied on interspecific comparisons of indirect measures of cognitive ability, such as brain size. We present direct evidence that individual variation in cognitive abilities is associated with differences in life span in a wild food caching bird. We measured the spatial cognitive abilities and tracked the life span of 227 mountain chickadees (Poecile gambeli) in their natural environment and found that individuals with better spatial learning and memory abilities involved in food caching lived longer. These results confirm that enhanced cognitive abilities can be associated with longer life in wild animals and that selection on cognitive abilities can lead to increased life span.

Spatial memory obviates following behaviour in an information centre of wild fruit bats.

According to the information centre hypothesis (ICH), colonial species use social information in roosts to locate ephemeral resources. Validating the ICH necessitates showing that uninformed individuals follow informed ones to the new resource. However, following behaviour may not be essential when individuals have a good memory of the resources' locations. For instance, Egyptian fruit bats forage on spatially predictable trees, but some bear fruit at unpredictable times. These circumstances suggest an alternative ICH pathway in which bats learn when fruits emerge from social cues in the roost but then use spatial memory to locate them without following conspecifics. Here, using an unique field manipulation and high-frequency tracking data, we test for this alternative pathway: we introduced bats smeared with the fruit odour of the unpredictably fruiting Ficus sycomorus trees to the roost, when they bore no fruits, and then tracked the movement of conspecifics exposed to the manipulated social cue. As predicted, bats visited the F. sycomorus trees with significantly higher probabilities than during routine foraging trips (of >200 bats). Our results show how the integration of spatial memory and social cues leads to efficient resource tracking and highlight the value of using large movement datasets and field experiments in behavioural ecology. This article is part of the theme issue 'The spatial-social interface: a theoretical and empirical integration'.

Of popsicles and crackers: when spatio-temporal memory is not integrated into children's decision-making.

Prior research has used innovative paradigms to show that some non-human animal species demonstrate behavioural choices (i.e. foraging for a food item at a specific location, and at a time that guarantees it has not yet decayed), reflecting episodic-like or 'WWW' memory (memory for 'what' happened, 'where' and 'when'). These results raised the question of whether similar approaches could be used to examine memory in young children in order to reduce verbal demands. The present research examines the extent to which children's WWW memory aligns with memory-based choices in 3- to 5-year-olds (n = 95; study 1) and in 7- to 11-year-olds and adults (n = 168; study 2). Results indicate that preschoolers' struggle with choice-based tasks probably reflects difficulty integrating their WWW memory with an understanding that certain items decay over time. Moreover, a convergence between verbal recall measures and choice-based measures is observable in 7-year-olds and beyond, reflecting a stronger integration of memory signals, understanding of state transformation, and decision-making. This article is part of the theme issue 'Elements of episodic memory: lessons from 40 years of research'.

FOS mapping reveals two complementary circuits for spatial navigation in mouse.

Here, we show that during continuous navigation in a dynamic external environment, mice are capable of developing a foraging strategy based exclusively on changing distal (allothetic) information and that this process may involve two alternative components of the spatial memory circuit: the hippocampus and retrosplenial cortex. To this end, we designed a novel custom apparatus and implemented a behavioral protocol based on the figure-8-maze paradigm with two goal locations associated with distinct contexts. We assessed whether mice are able to learn to retrieve a sequence of rewards guided exclusively by the changing context. We found out that training mice in the apparatus leads to change in strategy from the internal tendency to alternate into navigation based exclusively on visual information. This effect could be achieved using two different training protocols: prolonged alternation training, or a flexible protocol with unpredictable turn succession. Based on the c-FOS mapping we also provide evidence of opposing levels of engagement of hippocampus and retrosplenial cortex after training of mice in these two different regimens. This supports the hypothesis of the existence of parallel circuits guiding spatial navigation, one based on the well-described hippocampal representation, and another, RSC-dependent.

Knowing where to go: Spatial memory guides eye and body movements in a naturalistic visual search task.

Most research on visual search has used simple tasks presented on a computer screen. However, in natural situations visual search almost always involves eye, head, and body movements in a three-dimensional (3D) environment. The different constraints imposed by these two types of search tasks might explain some of the discrepancies in our understanding concerning the use of memory resources and the role of contextual objects during search. To explore this issue, we analyzed a visual search task performed in an immersive virtual reality apartment. Participants searched for a series of geometric 3D objects while eye movements and head coordinates were recorded. Participants explored the apartment to locate target objects whose location and visibility were manipulated. For objects with reliable locations, we found that repeated searches led to a decrease in search time and number of fixations and to a reduction of errors. Searching for those objects that had been visible in previous trials but were only tested at the end of the experiment was also easier than finding objects for the first time, indicating incidental learning of context. More importantly, we found that body movements showed changes that reflected memory for target location: trajectories were shorter and movement velocities were higher, but only for those objects that had been searched for multiple times. We conclude that memory of 3D space and target location is a critical component of visual search and also modifies movement kinematics. In natural search, memory is used to optimize movement control and reduce energetic costs.

The development of self-initiated visuo-spatial working memory.

Studies on the development of visuo-spatial working memory (VSWM) have focused almost exclusively on memory tasks in which children had no control over the content of the representations they memorized. In contrast, in everyday life children often select the items that they encode in memory. In the current study, we used two modified span tasks to explore the development of this aspect of memory, termed self-initiated (SI) VSWM, in children aged 7 to 10 years. In Experiment 1 participants memorized sequences of spatial locations, whereas in Experiment 2 participants memorized sequences of pictures of real-world objects and the spatial locations of the targets were irrelevant for task performance. In both experiments, participants either selected the targets they memorized themselves or memorized randomly selected targets that were provided to them. Previous studies in adults have shown that efficient processing in the SI condition in both tasks entails the construction of spatially structured representations. The results of the two experiments revealed that children constructed spatially structured representations with short paths between successive locations in the spatial sequences, fewer path crossings, and more linear shapes compared with the provided representations. Self-initiation benefited overall performance, especially in Experiment 1 where the memory task was more demanding. This study shows that 7- to 10-year-old children have access to the metacognitive knowledge on the spatial structure of VSWM and strategically impose structure during encoding to benefit memory performance. More generally, SI VSWM highlights an important aspect of behavior, demonstrating how children shape their environment to facilitate functioning.

Ovariectomy and Estradiol Supplementation Prevents Cyclophosphamide- and Doxorubicin-Induced Spatial Memory Impairment in Tumor-Bearing MMTV-PyVT Mice.

Chemotherapy-related cognitive impairments (CRCIs) encompass cognitive deficits in memory, attention, and executive function that arise during and following chemotherapy. CRCI symptoms are predominantly reported by female cancer patients but also occur in males. These impairments may involve reduced estradiol levels, which then increases vulnerability to the impact of tumors and chemotherapy on cognition. This study utilized the MMTV-PyVT mouse model of breast cancer to test the hypothesis that impaired ovarian function and associated estradiol levels play a critical role in CRCI susceptibility. Mice were either ovariectomized (OVX) or underwent sham surgery. The OVX group then received supplemental estradiol (E2) ad libitum in the drinking water to maintain physiological hormone levels. After tumor development, mice were trained in the Morris water maze to assess spatial memory, and subsequently, they received weekly injections of either saline or a combination of cyclophosphamide (CYP; 66.7 mg/kg, i.v.) and doxorubicin (DOX; 6.7 mg/kg, i.v.) for 4 weeks. Spatial memory was reassessed 10 d and then 35 d, after the final injections. Results demonstrated a significant disruption of normal ovarian cycling in sham-operated mice treated with CYP + DOX, as well as significant spatial memory impairments when compared with OVX mice supplemented with E2 This study suggests that chemotherapy-induced ovarian damage and the consequent drop in circulating estrogens significantly contribute to vulnerability to CRCIs, underscoring the importance of estradiol in mitigating CRCI risks.

Oligonol enhances brain cognitive function in high-fat diet-fed mice.

Oligonol, a low-molecular-weight polyphenol derived from lychee fruit, is well recognized for its antioxidant properties, blood glucose regulation, and fat mass reduction capability. However, its effect on the central nervous system remains unclear. Here, we investigated the effects of oligonol on brain in a high-fat diet (HFD) fed mouse model, and SH-SY5Y neuronal cells and primary cultured cortical neuron under insulin resistance conditions. HFD mice were orally administered oligonol (20 mg/kg) daily, and SH-SY5Y cells and primary cortical neurons were pretreated with 500 ng/mL oligonol under in vitro insulin resistance conditions. Our findings revealed that oligonol administration reduced blood glucose levels and improved spatial memory function in HFD mice. In vitro data demonstrated that oligonol protected neuronal cells and enhanced neural structure against insulin resistance. We confirmed RNA sequencing in the oligonol-pretreated insulin-resistant SH-SY5Y neuronal cells. Our RNA-sequencing data indicated that oligonol contributes to metabolic signaling and neurite outgrowth. In conclusion, our study provides insights into therapeutic potential of oligonol with respect to preventing neuronal cell damage and improving neural structure and cognitive function in HFD mice.

Overexpression of TIAM2S, a Critical Regulator for the Hippocampal-Medial Prefrontal Cortex Network, Progresses Age-Related Spatial Memory Impairment.

TIAM Rac1-associated GEF 2 short-form protein (TIAM2S) is abundant in specific brain tissues, especially in the hippocampus, a brain region critical for processing and consolidation of spatial memory. However, how TIAM2S plasticizes the microstructure and circuits of the hippocampus to shape spatial memory as a neuroplastic regulator during aging remains to be determined. In this study, transgenic mice overexpressing human TIAM2S protein (TIAM2S-TG mice) were included, and interdisciplinary approaches, such as spatial memory tests and multiparametric magnetic resonance imaging sequences, were conducted to determine the role and the mechanism of TIAM2S in age-related spatial memory deficits. Despite no changes in their neural and glial markers and neuropathological hallmark expression of the hippocampus, behavioral tests showed that the TIAM2S-TG mice, and not wild-type (WT) mice, developed spatial memory impairment at 18 months old. The T2-weighted and diffusion tensor image analyses were performed to further study the possible role of TIAM2S overexpression in altering the hippocampal structure or neuronal circlets of the mice, increasing their vulnerability to developing spatial memory deficits during aging. The results revealed that the 12-month-old TIAM2S-TG mice had hippocampal dysplasticity, with larger volume, increased fiber numbers, and changed mean fractional anisotropy compared to those in the age-matched WT mice. The fiber tractography analysis exhibited significantly attenuated structural connectivity between the hippocampus and medial prefrontal cortex in the TIAM2S-TG mice. In conclusion, overexpression of TIAM2S, a detrimental factor affecting hippocampus plasticity, causes attenuation of the connectivity within hippocampus-mPFC circuits, leading to age-related spatial memory impairment.

Arc and BDNF mediated effects of hippocampal astrocytic glutamate uptake blockade on spatial memory stages.

Glutamate is involved in fundamental functions, including neuronal plasticity and memory. Astrocytes are integral elements involved in synaptic function, and the GLT-1 transporter possesses a critical role in glutamate uptake. Here, we study the role of GLT-1, specifically located in astrocytes, in the consolidation, expression, reconsolidation and persistence of spatial object recognition memory in rats. Administration of dihydrokainic acid (DHK), a selective GLT-1 inhibitor, into the dorsal hippocampus around a weak training which only induces short-term memory, promotes long-term memory formation. This promotion is prevented by hippocampal administration of protein-synthesis translation inhibitor, blockade of Activity-regulated cytoskeleton-associated protein (Arc) translation or Brain-Derived Neurotrophic Factor (BDNF) action, which are plasticity related proteins necessary for memory consolidation. However, DHK around a strong training, which induces long-term memory, does not affect memory consolidation. Administration of DHK before the test session impairs the expression of long-term memory, and this effect is dependent of Arc translation. Furthermore, DHK impairs reconsolidation if applied before a reactivation session, and this effect is independent of Arc translation. These findings reveal specific consequences on spatial memory stages developed under hippocampal GLT-1 blockade, shedding light on the intricate molecular mechanisms, governed in part for the action of glia.

Long-term saturated fat-enriched diets impair hippocampal learning and memory processes in a sex-dependent manner.

Consumption of saturated fat-enriched diets during adolescence has been closely associated with the reduction of hippocampal synaptic plasticity and the impairment of cognitive function. Nevertheless, the effect of long-term intake of these foods has not yet been studied. In the present study, we have investigated the effect of a treatment, lasting for 40 weeks, with a diet enriched in saturated fat (SOLF) on i) spatial learning and memory, ii) hippocampal synaptic transmission and plasticity, and iii) hippocampal gene expression levels in aged male and female mice. Our findings reveal that SOLF has a detrimental impact on spatial memory and synaptic plasticity mechanisms, such as long-term potentiation (LTP), and downregulates Gria1 expression specifically in males. In females, SOLF downregulates the gene expression of Gria1/2/3 and Grin1/2A/2B glutamate receptor subunits as well as some proinflammatory interleukins. These findings highlight the importance of considering sex-specific factors when assessing the long-term effects of high-fat diets on cognition and brain plasticity.

Individual differences in spatial working memory strategies differentially reflected in the engagement of control and default brain networks.

Spatial locations can be encoded and maintained in working memory using different representations and strategies. Fine-grained representations provide detailed stimulus information, but are cognitively demanding and prone to inexactness. The uncertainty in fine-grained representations can be compensated by the use of coarse, but robust categorical representations. In this study, we employed an individual differences approach to identify brain activity correlates of the use of fine-grained and categorical representations in spatial working memory. We combined data from six functional magnetic resonance imaging studies, resulting in a sample of $155$ ($77$ women, $25 \pm 5$ years) healthy participants performing a spatial working memory task. Our results showed that individual differences in the use of spatial representations in working memory were associated with distinct patterns of brain activity. Higher precision of fine-grained representations was related to greater engagement of attentional and control brain systems throughout the task trial, and the stronger deactivation of the default network at the time of stimulus encoding. In contrast, the use of categorical representations was associated with lower default network activity during encoding and higher frontoparietal network activation during maintenance. These results may indicate a greater need for attentional resources and protection against interference for fine-grained compared with categorical representations.

Impaired Dynamics of Positional and Contextual Neural Coding in an Alzheimer's Disease Rat Model.

Background: The hippocampal representation of space, formed by the collective activity of populations of place cells, is considered as a substrate of spatial memory. Alzheimer's disease (AD), a widespread severe neurodegenerative condition of multifactorial origin, typically exhibits spatial memory deficits among its early clinical signs before more severe cognitive impacts develop. Objective: To investigate mechanisms of spatial memory impairment in a double transgenic rat model of AD. Methods: In this study, we utilized 9-12-month-old double-transgenic TgF344-AD rats and age-matched controls to analyze the spatial coding properties of CA1 place cells. We characterized the spatial memory representation, assessed cells' spatial information content and direction-specific activity, and compared their population coding in familiar and novel conditions. Results: Our findings revealed that TgF344-AD animals exhibited lower precision in coding, as evidenced by reduced spatial information and larger receptive zones. This impairment was evident in maps representing novel environments. While controls instantly encoded directional context during their initial exposure to a novel environment, transgenics struggled to incorporate this information into the newly developed hippocampal spatial representation. This resulted in impairment in orthogonalization of stored activity patterns, an important feature directly related to episodic memory encoding capacity. Conclusions: Overall, the results shed light on the nature of impairment at both the single-cell and population levels in the transgenic AD model. In addition to the observed spatial coding inaccuracy, the findings reveal a significantly impaired ability to adaptively modify and refine newly stored hippocampal memory patterns.

Spatial memory and frames of reference: How deeply do we rely on the body and the environment?

How do we mentally represent the world out there? Psychology, philosophy and neuroscience have given two classical answers: as a living space where we act and perceive, dependent on our bodies; as an enduring physical space with its feature, independent of our bodily interactions. The first would be based on egocentric frames of reference anchored to the body, while the second on allocentric frames of reference centred on the environment itself or on objects. This raises some questions concerning how deep the reliance on the body and the environment is when using these reference frames, and whether they are affected differently by the duration of time and the scale (small or large) of space. To answer these questions, I have brought empirical evidence of the effect of motor interference, blindness, environmental characteristics and temporal factors on egocentric and allocentric spatial representational capacity. The results suggest that egocentric representations are deeply rooted in the body, with its sensory and motor properties, and are closely linked to acting now in small-scale or peripersonal space. Allocentric representations are more influenced by environmental than by bodily characteristics, by visual than by motor properties, and seem particularly related to large-scale or extrapersonal space. In line with neurophysiological evidence and a Kantian perspective, it appears that we are endowed with an internal spatial representation system ready to structure environmental information for our purposes. To what extent this system is innate and pervasive in cognition and what is its relationship to the neural 'positioning' substrate discovered by O'Keefe and colleagues requires further scientific investigation.

Protective effect of menthol against thioacetamide-induced hepatic encephalopathy by suppressing oxidative stress and inflammation, augmenting expression of BDNF and α7-nACh receptor, and improving spatial memory.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that can occur in people with acute or chronic liver disease. Here, we investigated the effects of menthol, a natural monoterpene, on HE induced by thioacetamide (TA) in male Wistar rats. The rats received 200 mg/kg of TA twice a week for four weeks and were administered 10 mg/kg of menthol intraperitoneally daily for the same period. The results showed that menthol treatment reduced oxidative stress and inflammation in the livers and hippocampi of the rats that received TA. It also lowered the levels of ammonium and liver enzymes AST, ALT, ALP, and GGT in the serum of these animals and prevented liver histopathological damage. In addition, the expression and activity of acetylcholinesterase in the hippocampus of HE model rats were decreased by menthol. Likewise, this monoterpene reduced the expression of TLR4, MyD88, and NF-κB in the hippocampus while increasing the expression of BDNF and α7-nACh receptor. Menthol also reduced neuronal death in the hippocampal cornu ammonis-1 and dentate gyrus regions and reduced astrocyte swelling, which led to improved learning and spatial memory in rats with HE. In conclusion, the study suggests that menthol may have strong protective effects on the liver and brain, making it a potential treatment for HE and neurodegenerative diseases.

Protective effects of L-carnitine against beta-amyloid-induced memory impairment and anxiety-like behavior in a rat model of Alzheimer's disease.

Alzheimer's disease (AD), the most common cause of dementia, leads to neurodegeneration and cognitive decline. We investigated the therapeutic effects of L-carnitine on cognitive performance and anxiety-like behavior in a rat model of AD induced by unilateral intracerebroventricular injection of ß-amyloid1-42 (Aß1-42). L-carnitine (100 mg/kg/day) was administered intraperitoneally for 28 consecutive days. Following this, the open-field test, novel object recognition test, elevated plus-maze test, Barnes maze test, and passive avoidance learning test were used to assess locomotor activity, recognition memory, anxiety-like behavior, spatial memory, and passive avoidance memory, respectively. Plasma and hippocampal oxidative stress markers, including total oxidant status (TOS) and total antioxidant capacity (TAC), were examined. In addition, histological investigations were performed in the dentate gyrus of the hippocampus using Congo red staining and hematoxylin and eosin staining. The injection of Aß1-42 resulted in cognitive deficits and increased anxiety-like behavior. These changes were associated with an imbalance of oxidants and antioxidants in plasma and the hippocampus. Also, neuronal death and Aß plaque accumulation were increased in the hippocampal dentate gyrus region. However, injection of L-carnitine improved recognition memory, spatial memory, and passive avoidance memory in AD rats. These findings provide evidence that L-carnitine may alleviate anxiety-like behavior and cognitive deficits induced by Aß1-42 through modulating oxidative-antioxidant status and preventing Aß plaque accumulation and neuronal death.

Pregnancy history and estradiol influence spatial memory, hippocampal plasticity, and inflammation in middle-aged rats.

Pregnancy and motherhood can have long-term effects on cognition and brain aging in both humans and rodents. Estrogens are related to cognitive function and neuroplasticity. Estrogens can improve cognition in postmenopausal women, but the evidence is mixed, partly due to differences in age of initiation, type of menopause, dose, formulation and route of administration. Additionally, past pregnancy influences brain aging and cognition as a younger age of first pregnancy in humans is associated with poorer aging outcomes. However, few animal studies have examined specific features of pregnancy history or the possible mechanisms underlying these changes. We examined whether maternal age at first pregnancy and estradiol differentially affected hippocampal neuroplasticity, inflammation, spatial reference cognition, and immediate early gene activation in response to spatial memory retrieval in middle-age. Thirteen-month-old rats (who were nulliparous (never mothered) or previously primiparous (had a litter) at three or seven months) received daily injections of estradiol (or vehicle) for sixteen days and were tested on the Morris Water Maze. An older age of first pregnancy was associated with impaired spatial memory but improved performance on reversal training, and increased number of new neurons in the ventral hippocampus. Estradiol decreased activation of new neurons in the dorsal hippocampus, regardless of parity history. Estradiol also decreased the production of anti-inflammatory cytokines based on age of first pregnancy. This work suggests that estradiol affects neuroplasticity and neuroinflammation in middle age, and that age of first pregnancy can have long lasting effects on hippocampus structure and function.

The weekend warrior effect: Consistent intermittent exercise induces persistent cognitive benefits.

Exercise provides a range of cognitive benefits, including improved memory performance. Previously, we demonstrated that 14 days of continuous voluntary wheel-running exercise enables learning in a hippocampus-dependent Object Location Memory (OLM) task under insufficient, subthreshold training conditions in adult mice. Whether similar exercise benefits can be obtained from consistent intermittent exercise as continuous exercise is unknown. Here, we examine whether intermittent exercise (the weekend warrior effect: 2 days of exercise a week for 7 weeks) displays similar or distinct cognitive benefits as previously examined with 14 days of continuous exercise. We find that both continuous and intermittent exercise parameters similarly enable hippocampus-dependent OLM compared to the 2-day exercise control group. Mice receiving intermittent exercise maintained cognitive benefits following a 7-day sedentary delay, whereas mice that underwent 14 continuous days of exercise showed diminished cognitive benefits as previously reported. Further, compared to continuous exercise, intermittent exercise mice exhibited persistently elevated levels of the genes Acvr1c and Bdnf which we know to be critically involved in hippocampus-dependent long-term memory in the dorsal hippocampus. Together findings suggest that consistent intermittent exercise persistently enables hippocampal-dependent long-term memory. Understanding the optimal parameters for persistent cognitive function and the mechanisms mediating persistent effects will aid in therapeutic pursuits investigating the mitigation of cognitive ailments.

Enhancing spatial memory and pattern separation: Long-term effects of stimulant treatment in individuals with ADHD.

This study explores the under-researched domain of long-term stimulant treatment in children and adolescents diagnosed with attention deficit hyperactivity disorder (ADHD). The necessity for extended treatment duration, often accompanied by safety concerns and side effects leading to treatment discontinuation, underscores the significance of this investigation. Concurrently, comparative studies have revealed adverse impacts on vulnerable regions within the hippocampal formation, accompanied by behavioral perturbations. We employed computerized tests and virtual reality to assess spatial memory, pattern separation, and object recognition memory in a cohort of children diagnosed with ADHD receiving stimulant treatment. We compared their performance to a group of neurotypical peers. Our findings indicate that the ADHD group exhibited a lower performance in spatial memory, pattern separation, and object recognition memory than ND group. Intriguingly, a positive relationship emerged between the duration of stimulant treatment and performance in these variables. Notably, this improvement was not immediate to MPH treatment but becomes significant after 24 months of treatment. In contrast to previous comparative investigations, our study did not reveal a detrimental impact on spatial navigation, object recognition memory, or pattern separation, despite the known interplay of these cognitive processes with the hippocampal formation. These results shed new light on the nuanced effects of stimulant treatment in ADHD, underscoring the need for a more comprehensive understanding of long-term treatment outcomes.